1,4-disubstituted piperazines

ABSTRACT

PIPERAZINE DERIVATIVES OF THE FORMULA   1-((R,R&#39;&#39;-PHENYL)-C(=N-R&#34;)-),4-R&#34;&#39;&#39;-PIPERAZINE   WHEREIN R AND R&#39;&#39; ARE HYDROGEN, HYDROXY, LOWER ALKYL, LOWER ALKOXY HALOGEN OR TRIFLUOROMETHYL, R&#34; IS LOWER ALKYL, LOWER ALKENYL, CYCLOALKYL OR PHENYL OR R&#34;&#39;&#39; IS HYDROGEN, LOWER ALKYL, LOWER ALKENYL, CARBOALKOXY, FORMYL, BENZYL, OR CINNAMYL HAVE POTENT HYPOGLYCEMIC ACTIVITY.

3,793,322 Patented Feb. 19, 1974 United States Patent Oflice US. Cl.260268 C 11 Claims ABSTRACT OF THE DISCLOSURE Piperazine derivatives ofthe formula wherein R and R are hydrogen, hydroxy, lower alkyl,

lower alkoxy, halogen or trifluoromethyl, R" is lower alkyl, loweralkenyl, cycloalkyl or phenyl and R is hydrogen, lower alkyl, loweralkenyl, carboalkoxy, formyl, benzyl, or cinnamyl have potenthypoglycemic activity.

This application is a continuation-in-part of our patent applicationSer. No. 129,940, filed Mar. 31, 1972, now abandoned.

This invention relates to new organic compounds having valuablepharmacological activity and to a process for the preparation of saidcompounds. In particular, the invention relates to piperazinederivatives of the formula and their pharmaceutically acceptable,non-toxic acid addition salts, wherein:

R and R are hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, ortrifiuoromethyl and may be the same or different;

R" is lower alkyl, lower alkenyl, cycloalkyl, or phenyl,

and

R' is hydrogen, lower alkyl, lower alkenyl, carboalkoxy,

carboalkoxyalkyl, formyl, phenyl, halophenyl, cinnamyl, benzyl orbenzylhydryl.

The lower alkyl, lower alkoxy and lower alkenyl groups may be branchedor straight chained and contain up to 6 carbon atoms. The cycloalkylgroups contain from 3 to 7 carbon atoms in the ring which may also carrya lower alkyl substituent.

The carboalkoxy groups contain alkyl groups having from 1 to carbonatoms and include carbomethoxy, carbethoxy, carbopropoxy, carbobutoxyand the like.

Desirably, R and R are lower alkyl, preferably methyl, or halogen,preferably chloro; R may be hydrogen and R is then chloro, lower alkyl,preferably methyl, or trifluoromethyl; R" is lower alkyl, preferablyisobutyl, and R' is carbethoxy.

According to the process of this invention, the piperazines wereprepared by heating in an inert solvent an appropriately substitutedbenzimidoyl chloride of the with an appropriately substituted piperazineof the formula wherein R, R, R" and R' are the same as above, in thepresence of an alkaline agent such as a tertiary amine, an alkali amide,an alkali alkoxide or an alkali hydride.

The benzimidoyl chlorides were prepared by first preparing a benzamidefrom a corresponding benzoyl chloride and an amine under the standardSchotten-Baumann procedure and then converting this amide to thebenzimidoyl chloride by treatment with thionyl chloride or phosphoruspentachloride according to the procedure in Organic Syntheses,Collective vol. 4, p. 283 (1962).

The N-alkyl piperazines were prepared by reacting an alkyl halide withN-formylpiperazine in the presence of triethylamine to yield N -formyl-N-alkyl piperazine. Acid hydrolysis of this compound yielded the desiredN-alkyl piperazine in accordance with the procedure in ArchivesInternationales Pharmacodynamie et de Therapie, vol. 128, pp. 18-19(1960). The intermediate N-formyl piperazine was prepared by treatingpiperazine with formic acid to yield diformyl piperazine. The reactionof the diformyl compound with piperazine yielded the mono-formylderivative, N-formyl-piperazine.

The intermediate N-carboalkoxy-piperazines were prepared by treatingpiperazine with an equivalent amount of an alkyl chlorocarbonate.

The hydrochloride salts were sometimes obtained directly. Such saltscould be converted to the free bases from which the salts were preparedby treating the base in an inert solvent with the desired amount of acidto form either the mono or diacidic salt. Suitable acids for preparingsuch salts include hydrochloric, hydrobromic, phosphoric, sulfuric,benzoic, mandelic, cinnamic, acetic, propionic, lactic, citric,tartaric, malic, malonic, succinic, maleic, and fumaric acids.

I The invention will be more fully illustrated in the examples thatfollow. These examples are given by way of illustration and are not tobe considered as limiting.

EXAMPLE 1 N -methyl N -[3-methyl-(N-isobutyliminobenzyl)]- piperazinedihydrochloride To a solution of 5.0 g. (0.05 mol) of N-methylpiperazine and 5.1 g. (0.05 mol) of triethylamine in ml. of dry benzenewas added 10.4 g. (0.05 mol) of 3-methyl-N- isobutylbenzimidoyl chlorideover a period of 15 minutes. The reaction mixture was then stirred atroom temperature for an additional 2 hrs. After the triethylaminehydrochloride was removed by filtration, concentration of the solutionafforded a yellow oily residue which was subsequently treated withdilute aqueous sodium hydroxide and then extracted with 250 ml. ether.Concentration of the dried ether layer and distillation of the residueaiforded N methyl N -[Fl-methyl-(N-isobutyliminobenzyl)]-piperazine,B.P. 1l214 (0.4 mm.) in 50% yield (8.2 g.). Introduction of HCl into anethereal solution of the base gave the corresponding dihydrochloridesalt. Recrystallization from acetonitrile yield 8.9 g. (57%) of product,M.P. 234-40.

EXAMPLE 2 N -carbethoxy-N -[3-methyl-(N-isobutyliminobenzyl) piperazinehydrochloride To a solution of 7.5 g. (0.05 mol) of carbethoxypiperazinein 100 ml. dry benzene was added 11.5 g. (0.05 mol) of3-methyl-N-isobutylbenzimidoyl chloride over a period of 15 minutes. Thereaction mixture was refluxed for 1 hour and then cooled. Filtrationyielded 14.3 g. of the crude product. Two recrystallizations fromacetone-ether afforded N -carbethoxy-N-[3-methy1-(N-isobutyliminobenzyl)]-piperazine hydrochloride, M.P.182-3, in 44% yield (8.3 g.).

EXAMPLE 3 N -benzhydryl-N (N-cyclohexyliminobenzyl) -piperazine EXAMPLE4 N -(n-hexyl)-N -(N-isobutyliminobenzyl) piperazine dimaleate To asolution of 13.6 g. (0.08 mol) of n-hexylpiperazine and 8.1 g. (11.2ml.), (0.08 mol) of triethylamine in 120 ml. toluene, was added 15.6 g.(0.08 mol) of N-isobutylbenzimidoyl chloride over a period of 15minutes. The reaction mixture was stirred at room temperature for aperiod of 2 hours. The triethylamine hydrochloride was filtered off andthe filtrate concentrated under vacuum. The residual oily base waswashed with 20 ml. water,

extracted with 50 ml. ether and dried over anhydrous magnesium sulfate.The dry ethereal solution was then added to a solution of 18.6 g. (0.16mol) maleic acid in 800 ml. ether to obtain the dimaleate salt. Tworecrystallizations from ethanol yielded 22.5 g. (50.2%) of product, M.P.175-6.

In accordance with the procedures described above and set forth in theexamples, the compounds in Table I below were prepared.

TABLE I N-R" -11HCl R R R" R" 'n M P. o

l-But Me 2 190-5 i-But Me 2 250-2 i-But Me 2 243- i-But Me 2 233-5 i-ButMe 2 251-3 i-But Me 2 242-4 i-But Me 2 198-202 i-But Me 2 300 i-Bnt Me 2260-5 i-But; Me 2 300 i-But Me 2 297-9 i-But Me 2 239-242 i-But Me 2 300i-But Me 2 243-5 n-Pr Me 2 248-50 Allyl Me 2 223-5 Cyclohex Me 2 240-2Cyclohex Me 2 252-5 i-Am Me 2 235-243 i-Arn Me 2 22 n-Hex Me 2 250-2 MeE1: 2 239- 4 n-Pr Et 2 263-5 n-But Et 2 279-81 Allyl Et 2 278-80 i-ButEt 2 270-2 i-But Et 2 247-49 l-Bllt Et 2 252-3 Me CODE: 1 227-8 Me CODE;1 214-5 Et 0001111; 1 237-8 Allyl 000191 1 220-1 n-Pr COOEt 1 229-232n-But COOEt 1 204-6 i-Am COOEts 1 143-4 i-But; 000111; 1 196-8 i-But000191; 1 180-1 i-But 000131 1 170. 5-171.5 i-But COOEt 1 186-8 l-But000m 1 197-8 i-But COOEt 1 132-3 i-But COOEt 1 185-7 i-But COOEt 1 162-3TABLE I-C0n tinued R R R" R n M.P; C

H i-But COOEt 1 171-3 H Cyclohex COOEt 1 222-4 H Ph COOEt 1 222-5 H PhCOOEt 1 207-9 H l-But n-Hex 2 2 142-3 H. i-But n-Hex 2 162-3 E. i-Butn-Hex 9 2 131-2 H- i-But n-Hex 5 2 99-101 H- i-Am n-Hex 2 2 167-8 E n-Prn-Hex 5 2 157-8 E Allyl n-Hex 2 2 144-5 H Cyclohex n-Hex E 2 168-9 E hn-Hex 3 2 169-170 H 3,4-diMePh n-Hex 2 223-5 H i-But D-Cl-GeHs 1 273-5 Hl-But lJ-Cl-CeH; 1 254-6 H o-Cl i-But 11-61-0011! 1 218-220 H.- p-GF;i-But p-Cl-(XH; 1 253-6 H-- H l-But Ph 2 218-221 H.- H i-But Benzhydryl-52 H- H n-Pr B enzhydryl 1 230-32 H-.. H Me Benzhydryl 1 216-19 H.- HPh Benzhydryl 166-8 H.. H i-But Benzyl l 2 168-9 H.. o-Me l-But Benzyl 12 168-179 H- H i-But 2,4-d1-C1 benzyl 1 2 161-3 H H i-But 2384-1711(lMeO) 2 226-7 enzy o-Me i-Bul; CH0 1 230-231 m-Me i-But CH0 1 194-6i-But CH0 1 254-6 i-But H 2 225-7 i-But H 2 231-2 i-But H 2 250-252i-But Allyl 2 -5 1 Hydroiodide salt. 2 Maleate salt. Melting point isthat of the free base.

TABLE II Percent reduction of blood R" R" glucose i-But 002151; 31. 5i-But COsEt 29. 4 i-But COzEt 43. 2 i-But CO2Et 49 i-But 002131; 30. 5i-But Allyl 29 l-But Me 36 i-But Me 35. 8 i-Am Me 31. 9 i-But CHO 33. 7i-But Benzyl l 33. 9 i-But G01Et 30. 8

1 At 25 mgJkg. p.o.

In addition to possessing hypoglycemic activity certain compounds alsopossessed strong anti-arrhythmic activity which would make them usefulin the treatment of auricular fibrillation and other heart conditionsassociated with arrhythmia. These compounds included N -methyl-N[(N-cyclohexyl)-iminobenzyl] piperazine, N carbethoxy N[N-isoamyl)-iminobenzyl]-piperazine, N -pchlorophenyl N[(N-isobutyl)-iminobenzyl]-piperazine, N -(n-hexyl) N(N-isobutyliminobenzyl)-piperazine, and N -(n-hexy1)-N -(N-3,4dimethylphenylirninobenzyl)-piperazine.

The compounds can be mixed with solid or liquid pharmaceutical carriersand formulated into tablets, powders or capsules, for oraladministration or dissolved in suitable solvent for either oral orparenteral administration.

We claim:

1. A compound of the formula wherein:

R and R are hydrogen, methyl, methoxy, or halogen and may be the same ordifferent; or when R is hydrogen, R may also be lower alkyl, loweralkoxy or trifluoromethyl;

R" is lower alkyl, allyl, cycloalkyl having from 3 to 7 carbon atoms, orphenyl; and

R" is lower alkyl, allyl, carboalkoxy wherein the alkoxy group has from1 to 5 carbon atoms, formyl, halophenyl, benzyl or benzhydryl;

and its pharmaceutically acceptable, non toxic acid addition salts.

2. The compound according to claim 1, wherein R is hydrogen and R iso-methyl.

3. The compound according to claim 1, wherein R" is isobutyl.

4. The compound according to claim 1, wherein R' is carboethoxy.

5. The compound according to claim 1, wherein R is hydrogen,

R' is o-chloro,

R" is i-butyl, and

R'" is carboethoxy.

6. The compound according to claim 1, wherein R is Z-methyl,

R is 6-methyl,

R" is i-butyl, and

R'" is carboethoxy.

7. The compound according to claim 2, wherein R" is i-butyl and R" ismethyl.

6 8. The compound according to claim 2, wherein R is i-butyl and R isbenzyl. 9. The compound according to claim 2, wherein R" is i-butyl andR" is formyl. 10. The compound according to claim 3 wherein R and R arehydrogen and R" is n-hexyl. 11. The compound according to claim 1wherein R and R are hydrogen, R" is 3,4-dimethy1phenyl, and R' isn-hexyl.

References Cited UNITED STATES PATENTS 3,068,236 12/1962 Krapcho 260268PH 3,148,209 9/1968 Krapcho 260268 PH 3,406,170 10/1968 Papes 260268 RI3,431,304 4/1969 Fryer 260268 R 3,468,882 7/1969 Laskowsky 260268 PH3,492,331 1/1970 Saig 260 268 R 3,646,029 2/1972 Mullins 260268 R DONALDG. DAUS, Primary Examiner US. Cl. X.R.

Disclaimer 3,793,322.James R. Shrofl, Bronx, N.Y., and View?" Bandm'oo,Sommerville, NJ. 1,4-DISUBSTITUTED PIPERAZINES. Patent dated Feb. 19,1974. Disclaimer filed Mar. 14, 1975, by the assignee, USVPharmaceutz'cal Uorpomtion.

Hereby enters this disclaimer to claims 1-9, inclusive, and claim 11 ofsaid patent.

[Official Gazette July 22, 1975.]

